Adiponectin Actions on the Monocyte to Reduce Atherosclerosis

描述(申请人提供)：脂联素，一种主要由脂肪组织产生的激素，已成为西方世界两大疾病--糖尿病和心血管疾病的治疗靶点。脂联素具有抗糖尿病、抗炎和抗动脉粥样硬化的特性，但在肥胖、胰岛素抵抗、2型糖尿病和心血管疾病中以低水平循环。虽然越来越多的数据表明脂联素在血管细胞中具有多效性，但脂联素及其受体在单核/巨噬细胞炎症和动脉粥样硬化中的作用尚不清楚。我们已经产生了令人兴奋的新数据，证明1)与胰岛素敏感的受试者相比，胰岛素抵抗的单核细胞有更多的促炎基因表达，2)两种脂联素受体都在单核细胞上表达，并在胰岛素抵抗时增加，3)脂联素激活单核细胞5‘-磷酸腺苷激活的激酶(AMPK)抑制肿瘤坏死因子-1激活的炎症基因，以及4)腺病毒脂联素的应用抑制加速的动脉粥样硬化和促进现有的动脉粥样硬化的消退。该项目的主要假设是，血浆脂联素的变化与单核/巨噬细胞基因的关键变化有关，这些基因介导炎症、泡沫细胞的形成，并最终影响血管炎症、动脉粥样硬化的进展和消退。本项目的具体目标是：1)确定调节单核/巨噬细胞中脂联素受体AdipoR1和AdipoR2的特定炎症和代谢因子；2)确定调控人和小鼠单核/巨噬细胞中单核/巨噬细胞功能、炎症基因表达和泡沫细胞形成的脂联素基因靶点，并确定AMPK和PPAR-1信号通路在这些过程中的作用；以及3)确定腺病毒脂联素和依赖于脂联素的PPAR3配体和脂联素依赖的PPAR3配体在动脉粥样硬化加速进展(血管紧张素II注射LDLR/和old-LDLR/-)和退化(old-LDLR-/-)模型中的作用用AdipoR1/R2基因敲除小鼠骨髓移植研究巨噬细胞脂联素受体在血管炎症和动脉粥样硬化中的作用。该项目将对确定脂联素及其受体在单核/巨噬细胞中的特定保护作用，在单核/巨噬细胞中识别潜在的新的脂联素候选基因靶点，以及确定这些基因在延缓或促进小鼠心血管疾病模型中动脉粥样硬化的进展或消退中的作用将是重要的。本文提出的研究将为我们理解脂联素、它作为代谢综合征治疗靶点的潜在重要性以及它对糖尿病和冠状动脉疾病的后果提供重要的新见解。与公共健康相关：脂联素是一种主要由脂肪组织产生的激素，已成为糖尿病和心血管疾病这两种主要疾病的关键治疗靶点。该项目将对确定脂联素及其受体在单核/巨噬细胞中的特定保护作用，在单核/巨噬细胞中寻找潜在的新的脂联素候选靶基因，以及确定这些基因在延缓或促进小鼠心血管疾病模型中动脉粥样硬化的进展或消退中的作用将是重要的。本文提出的研究将为我们理解脂联素、它作为代谢综合征治疗靶点的潜在重要性以及它对糖尿病和冠状动脉疾病的后果提供重要的新见解。

DESCRIPTION (provided by applicant): Adiponectin, a hormone produced primarily by adipose tissue, has emerged as a therapeutic target for two major diseases of the Western World, diabetes and cardiovascular disease. Adiponectin has antidiabetic, antiinflammatory and antiatherogenic properties, but circulates in low levels in obesity, insulin resistance, type 2 diabetes and cardiovascular disease. Although increasing data demonstrate pleiotropic effects of adiponectin in vascular cells, the role of adiponectin and adiponectin receptor expression in monocyte/macrophage inflammatory and atherogenic properties remain unclear. We have generated exciting new data demonstrating that 1) monocytes of insulin resistant vs. insulin sensitive subjects have more proinflammatory gene expression, 2) both adiponectin receptors are expressed on the monocyte and are increased in insulin resistance, 3) adiponectin activates monocyte 5' adenosine mono phosphate-activated kinase (AMPK) suppressing inflammatory genes activated by tumor necrosis factor-1, and 4) administration of adenoviral adiponectin inhibits accelerated atherosclerosis and promotes regression of existing atherosclerosis in mouse models. The major hypothesis of this project is that alterations in plasma adiponectin are associated with key changes in monocyte/macrophage genes that mediate inflammation, foam cell formation and that ultimately influence vascular inflammation, atherosclerosis progression and regression. The specific aims of this project are to: 1) define specific inflammatory and metabolic factors that regulate the adiponectin receptors, AdipoR1 and AdipoR2 in monocyte/macrophages, 2) define adiponectin gene targets that regulate monocyte/macrophage function, inflammatory gene expression, and foam cell formation in human and mouse monocyte/macrophages and determine the role of the AMPK and peroxisome proliferator activated receptor(PPAR)-1 signaling pathways in these processes, and 3) determine adenoviral adiponectin and adiponectin-dependent PPAR3 ligand effects in models of accelerated atherosclerosis progression (angiotensin II-infused LDLR-/- and old-LDLR-/-) and regression (old-LDLR-/-), and the role of macrophage adiponectin receptors in vascular inflammation and atherosclerosis using bone marrow transplantation with AdipoR1/R2 knockout mice. This project will be important to define specific protective actions of adiponectin and its receptors in the monocyte/macrophage; to identify potentially new candidate gene targets of adiponectin in monocyte/macrophages; and to define the role of these genes in attenuating the progression or promoting the regression of atherosclerosis in mouse cardiovascular disease models. The studies proposed herein will provide important new insights into our understanding of adiponectin, its potential importance as a therapeutic target in the metabolic syndrome, and its consequences for diabetes and coronary artery disease. PUBLIC HEALTH RELEVANCE: Adiponectin, a hormone produced mainly by the adipose tissue, has emerged as a key therapeutic target for two major diseases, diabetes and cardiovascular disease. This project will be important to define specific protective actions of adiponectin and its receptors in the monocyte/macrophage; to identify potentially new candidate target genes of adiponectin in monocyte/macrophages; and to define the role of these genes in attenuating the progression or promoting the regression of atherosclerosis in mouse cardiovascular disease models. The studies proposed herein will provide important new insights into our understanding of adiponectin, its potential importance as a therapeutic target in the metabolic syndrome, and its consequences for diabetes and coronary artery disease.